The present invention relates to a crystalline form of amrubicin hydrochloride which is useful as a drug.
Japanese Patent KOKOKU(Examined) 3-5397 and U.S. Pat. No. 4,673,668 disclose the preparation of (7S,9S)-9-acetyl-9-amino-7-[(2-deoxy-xcex2-D-erythro-pentapyranosyl)oxy]-7,8,9, 10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione hydrochloride and its usage as a cancer-chemotherapeutical agent, which is referred to as xe2x80x9camrubicin hydrochloridexe2x80x9d hereinafter and is represented by the formula: 
However, these Patents do not specifically disclose thermally stable crystalline amrubicin hydrochloride.
Japanese Patent 2,603,480 and U. S. Pat. No. 4,952,566 disclose stable preparations of amrubicin hydrochloride containing agents such as L-cysteine. These patents disclose preparations for stabilized injection, but do not disclose the stabilization of amrubicin hydrochloride itself as a medicine or a bulk drug.
The inventors of the present invention have intensively carried out research on the crystalline forms of amrubicin hydrochloride, and found that a specific crystal form of amrubicin hydrochloride which is referred to as xe2x80x9cxcex2-type crystalline amrubicin hydrochloridexe2x80x9d hereinafter, has excellent thermal stability. Thus, the present invention has been accomplished.
Accordingly, the objects of the present invention are as follows:
[1] A crystalline amrubicin hydrochloride having a powder X-ray diffraction pattern as given in Table 1
[2] A process of preparing a crystalline amrubicin hydrochloride according to [1] comprising crystallizing amrubicin hydrochloride at a temperature of 15xc2x0 C. or above.
[3] A process according to [2] comprising crystallizing amrubicin hydrochloride from a mixture of (a) hydrophilic organic solvent and (b) a solution of amrubicin hydrochloride in water or a mixture of water and hydrophilic organic solvent, at a temperature of 15xc2x0 C. or above.
[4] A process according to [2] comprising:
(1) dissolving amrubicin hydrochloride in water or a mixture of water and hydrophilic organic solvent;
(2) adjusting the pH of the solution to a value of from pH 1.5 to pH 4;
(3) crystallizing amrubicin hydrochloride by adding the solution to hydrophilic organic solvent at a temperature of 15xc2x0 C. or above, preferably up to 50xc2x0 C.
[5] A process according to [2], [3] or [4], wherein the crystallization temperature is 22xc2x0 C. to 40xc2x0 C.
[6] A process according to [3], [4] or [5], wherein the hydrophilic organic solvent (a) is acetone, isopropanol or acetonitrile.
[7] A process of preparing a freeze-dried preparation of amrubicin hydrochloride, comprising dissolving crystalline amrubicin hydrochloride according to [1] in water, and freeze-drying the dissolved amrubicin hydrochloride.
[8] A process according to [7] comprising:
(1) dissolving crystalline amrubicin hydrochloride according to [1] and L-cysteine or a salt thereof in water;
(2) adjusting the pH of the solution to a value of from pH 2 to pH 5; and
(3) freeze-drying the dissolved amrubicin hydrochloride.
[9] Use of crystalline amrubicin hydrochloride according to [1] in the production of a freeze-dried pharmaceutical formulation.
[10] A crystalline amrubicin hydrochloride according to [1] for use in the treatment of the human or animal body by therapy.
[11] Use of a crystalline amrubicin hydrochloride according to [1] in the preparation of a medicament comprising a freeze-dried form thereof for use in the treatment of cancer by injection of said freeze-dried form into a patient in need of such treatment.
[12] A pharmaceutical composition comprising a crystalline amrubicin hydrochloride according to [1] and a pharmaceutically acceptable carrier.
[13] A method of treating cancer comprising administrating to a person in need thereof, a freeze-dried preparation of amrubicin hydrochloride prepared according to [7] or [8].
[14] A method of treating cancer comprising administrating to a person in need thereof, a pharmaceutical composition according to [12].